Microencapsulation of protein drugs has been the method of choice for developing long-term delivery formulations. The current methods of microencapsulation, especially solvent extraction and solvent evaporation methods, were not initially developed for microencapsulation of protein drugs, and for this reason they present a number of difficulties in protein microencapsulation. Only a selected number of protein drugs have been microencapsulated using the conventional methods.The objective of this project is to develop new microencapsulation technologies based on the "solvent exchange method" that we recently found. In the solvent exchange method, individual aqueous protein microdroplets are coated with biodegradable poly(lactic-co-glycolic acid) (PLGA) to form true microcapsules in a fraction of a second using the ink-jet technology. Because of the extremely short time period for microencapsulation, most protein drugs do not interact with PLGA and solvent. The hypothesis to be tested in this project is that formation of PLGA microcapsules on aqueous protein microdroplets depends on the spreading coefficient of a hydrophilic solvent on an aqueous surface and the water-solubility of the solvent. The specific aims of this project are: (1) to optimize the microencapsulation process using the solvent exchange/ink-jet technology; (2) to find the best processable PLGA/solvent systems for forming PLGA microcapsules; (3) to find the optimum physicochemical properties of aqueous microdroplets for formation of stable microcapsules and preservation of protein drugs; (4) to prepare microcapsules loaded with protein drugs, such as human growth hormone and erythropoietin, and examine the stability of the loaded drugs, their release kinetics, and their long-term stability; and (5) to examine the bioactivity of the protein drugs after release from microcapsules.The significance of this project is that a new microencapsulation method that is specifically designed for protein drugs will be developed. Because of the simplicity of the solvent exchange method, it is expected to open a new avenue of microencapsulation of protein drugs with various properties.